Parkinson S Repository of Biosamples and Networked Datasets

Parkinson’s Repository of Biosamples and Networked Datasets

PRoBaND

(Tracking Parkinson’s)

Running title:PRoBaND

Protocol Version:1.5

Date:24/06/2016

REC Reference Number:11/AL/0163

Sponsor’s Protocol Number:GN11NE062

Sponsors:NHS Greater Glasgow & Clyde and The University of Glasgow

Funder:Parkinson’s UK

This study will be performed according to the Research Governance Framework for Health and Community Care (Second edition, 2006) and WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects 1964 (as amended).

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Contacts

Chief Investigator

Dr Donald Grosset
Consultant Neurologist
NHS Greater Glasgow & Clyde
Queen Elizabeth University Hospital
1345 Govan Road
Glasgow, G51 4TF
E-mail:

Tel: 0141 201 2486

Co-investigators

Professor David Burn

Professor David Burn

Clinical Ageing Research Unit

NewcastleUniversity

Campus for Ageing and Vitality

Newcastle Upon Tyne NE4 5PL

E-mail:
Tel: 0191 248 1266

Professor. Roger Barker

University of Cambridge

12 Union Road

Cambridge CB2 1EZ

E-mail:
Tel: 01223 337733

Professor Nicholas Wood

UniversityCollegeLondon

Department of Molecular Neuroscience

Queen Square

London WC1N 3BG

E-mail:
Tel: 020 7837 3611 Ext 4255

Prof. Nin Bajaj

Department of Neurology

Nottingham University Hospital

Hucknall Road

Nottingham NG5 1PB

E-mail:
Tel: 0115 969 1169

Dr Tom Foltynie

National Hospital for Neurology & Neurosurgery

Queen Square

London WC1N 3BG

E-mail:

Tel: 0203 108 0026

Professor. Huw Morris

Department of Clinical Neurosurgery

UCL Institute of Neurology

Upper 3rd Floor

Royal Free Hospital

Rowland Hill Street

London NW3 2PF

E-mail: or

Tel: 020 7794 0500 Ext 36833

Dr Nigel Williams

See below under Laboratories

Trial Statisticians

Professor Yoav Ben-Shlomo
University of Bristol

39 Whatley Road

Bristol BS8 2PS

E-mail:

Tel: 0117 9928 7206

Mr Michael Lawton

Research Assistant in MedicalStatistics
University of Bristol

39 Whatley Road

Bristol BS8 2PS

E-mail:

Tel: 0117 9287 255

Central Data Co-ordinator

Dr Katherine Grosset

Department of Neurology

Queen Elizabeth University Hospital

1345 Govan Road

Glasgow G51 4TF

E-mail:

Tel: 0141 232 7846

Project Manager/Study Co-ordinator

Mrs Alison Smith

Department of Neurology

Queen Elizabeth University Hospital

1345 Govan Road

Glasgow G51 4TF

E-mail:

Tel No: 0141 201 2486

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Sponsor’s representative

Ms Joanne McGarry
Academic Research Co-ordinator
NHS Greater Glasgow & Clyde
Research and Development Management Office
West Glasgow Ambulatory Care Hospital
Dalnair Street
Glasgow G3 8SW

E-mail:

Tel: 0141 232 1818

Funding Body

Parkinson’s UK

215 Vauxhall Bridge Road

London SW1V 1EJ

E-mail:
Tel: 0207 931 8080

Laboratories

Dr Nigel Williams

Institute for Psychological Medicine & Clinical Neurosciences

CardiffUniversitySchool of Medicine

HaydnEllisBuilding

Maindy Road

Cathays

CardiffCF24 4HQ

E-mail:

Tel No: 02920687070

ECACC

Genetic Support Services

Health Protection Agency
Centre for Emergency Preparedness & Response

Porton Down
Salisbury
Wiltshire SP4 0JG
Email:

Tel: +44 (0)1980 612512

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Protocol Approval

PRoBaND: Parkinson’s Repository of Biosamples and Network Datasets

Chief Investigator: Dr. Donald Grosset
Institute of Neurological Sciences
Queen Elizabeth University Hospital
1345 Govan Road
Glasgow G51 4TF

Signature:

Date: 18/01/2017

Sponsor’s representative Ms Joanne McGarry
Academic Research Co-ordinator
NHS Greater Glasgow & Clyde
Research and Development Management Office
West Glasgow Ambulatory Care Hospital
Dalnair Street
Glasgow G3 8SW

Signature:

Date:

Parkinson’s Repository of Biosamples and Networked Datasets

PRoBaND

Contacts

Protocol Approval

TABLE OF CONTENTS

ABBREVIATIONS

STUDY SYNOPSIS

STUDY FLOW CHART 1 - Patients diagnosed for less than three years

STUDY FLOW CHART 1A- Interim Extension

STUDY FLOW CHART 2- Patients with PD onset at less than age 50 years

STUDY FLOW CHART 3- Relatives of PD patients

1.0INTRODUCTION

Parkinson’s disease epidemiology

Parkinson’s disease genetics

Parkinson’s disease phenomenology

Genetic sub-types of PD

Recording and scoring key PD features in the PRoBaND study

Requirement for large sample sizes in PD research

Combining datasets

PRoBaND

STUDY RATIONALE - HYPOTHESIS

The interim extension of the main study will continue the hypotheses, to further define variations in progression rate linked to biosamples.

2.0STUDY OBJECTIVES

3.0 STUDY DESIGN

3.1 STUDY POPULATION

3.2 MAIN INCLUSION CRITERIA

3.3 MAIN EXCLUSION CRITERIA

3.4 IDENTIFICATION OF PARTICIPANTS AND CONSENT

3.5 STUDY SCHEDULE

3.6 BLOOD TESTING / VENEPUNCTURE

4.0 GENETIC TESTING PROCESS

5.1 DATA COLLECTION

5.2 STUDY TIMESCALE

5.3 STATISTICAL ANALYSIS

Power calculation.

6.0 SOURCE DATA & DOCUMENTS

7.0 STUDY MANAGEMENT

Steering Group

Data and Biosample Access Committee

Independent International Review Committee

8.0 STUDY AUDITING

9.0 PROTOCOL AMENDMENTS

10.0 ETHICAL CONSIDERATIONS

Ethical conduct of the study

Informed consent

11.0 INDEMNITY AND INSURANCE

12.0 FUNDING

13.0 SPONSOR RESPONSIBILITIES

14.0 ANNUAL REPORTS

15.0 DISSEMINATION OF FINDINGS

16.0 REFERENCES

APPENDIX 1. ASSESSING THE L-DOPA RESPONSE

APPENDIX 2

ABBREVIATIONS

AE / Adverse event
CDE / Common data elements
CRF / Case report form
COMT / Catechol-O-methyl transferase
DaTSCAN / Dopamine transporter brain scan
DeNDRoN / Dementia and Neurodegenerative Diseases Research Network
eCRF / Electronic case record form
EDTA / Ethylene Diamine Tetra-acetic Acid
EC / Ethics Committee
FPCIT / Fluoro-propyl carbomethoxy iodophenyl tropane, also known as Ioflupane
(and also known as DaTSCAN)
GBA / Glucocerebrosidase
GP / General Practitioner
ICH GCP / International Conference on Harmonization of Good Clinical Practice
LREC / Local regional ethics committee
LRRK2 / Leucine-rich repeat kinase 2
MAPT / Microtubule-associated protein tau
MDS / Movement disorder society
MoCA / Montreal cognitive assessment
MREC / Multi regional ethics committee
NINDS / National Institute for Neurological Diseases and Stroke
NMS / Non-motor symptoms
PD / Parkinson’s disease
PDQ8 / Parkinson’s disease quality of life scale
PET / Positron emission tomography
PPMI / Parkinson’s progression markers initiative
QoL / Quality of life
REM / Rapid eye movement
SAE / Serious adverse event
SCOPA-AUT / Scales for outcomes in Parkinson’s disease - autonomic
SPECT / Single photon emission computed tomography
SUSAR / Suspected Unexpected Serious Adverse Reaction
UPDRS / Unified Parkinson's Disease Rating Scale

STUDY SYNOPSIS

Title of Study: / PRoBaND: Parkinson’s Repository of Biosamples and Networked Datasets (Tracking Parkinson’s)
Coordinating Study Centre: / Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow
Duration of Study: / 9 years
Objectives: / To identify genetic and biomarker factors which affect the expression of Parkinson’s Disease.
Primary Objective: / To define the severity and rates of progression of clinical features of Parkinson’s Disease.
Secondary Objective: / To relate clinical phenomenology of Parkinson’s disease to genetic and biomarker changes.
Study Endpoints / Primary endpoint
Proportion of patients with PD who have gene mutation related to the expression of their disease.
Main Secondary endpoint
Progression rate of key PD features: motor, non-motor, therapy response, cognitive.
Rationale: / PD has varied expression with likely genetic causes.
Methodology: / Prospective multi-centre observational trial.
Sample Size: / 3080
Registration/Randomisation: / 4:1 active to control for relatives of gene test positive index PD cases.
Inclusion Criteria /

PD diagnosed within 3 years
PD diagnosis at age under 50
First degree relative of same.

Exclusion Criteria / Other Parkinson disorder, dementia.
Duration of Treatment: / Not applicable
Statistical Analysis /

5 - 8 % difference for categorical variables detected in 2000 patients assuming 90% power and 5% significance
For continuous measures, 0.33 standardised difference with 200 cases and 200 controls (sampling 10% of the cohort based on a specific feature e.g. gene mutation).
Comparing gene positive and gene negative relatives, 0.42 standardised difference between 100 cases and 150 relatives.

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STUDY FLOW CHART 1 - Patients diagnosed for less than three years

Screening visit / (Baseline) Visit 1 / Visit
2 / Visit
3 / Visit
4 / Visit
5 / Visit
6 / Visit
7
0months / 6 months / 12 months / 18 months / 24 months / 30 months / 36 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medical/Disease history / X
Medications review / X / X / X / X / X / X / X
Vital signs (blood pressure, weight) / X / X
Height / X
Family history / X
Demographics / X
Blood sample for DNA / X
Blood sample for serum / X / X / X
QOL questionnaires / X / X / X
Depression questionnaire / X / X / X
Parkinson’s Rating Score / X / X / X
Social history / X
Non-motor symptom score / X / X / X
PD grading / X / X / X
Diagnostic features / X / X / X
Parkinson’s sleep scale / X / X / X
Epworth sleep score / X / X / X
REM sleep disturbance / X / X / X
Impulsive questionnaire / X / X / X
Clinical and Global impression / X / X
Constipation questionnaire / X / X / X
Cognitive testing / X / X / X
Smell testing / X
Autonomic features / X / X / X
Personality questionnaire / X
Environmental exposure questionnaire / X
Diagnostic factors / X
L-dopa challenge test * / X
Scans ** / X / X
Tissue Bank / X / X
Wearing off questionnaire / X

* L-dopa challenge test will be performed once during the study, in patients who are prescribed L-dopa based treatment. It will be performed in patients who have been on L-dopa for at least 6 months, by scoring the UPDRS part 3 after overnight “off“, and after unit dose of L-dopa.

** Structural brain imaging and functional brain imaging. Results of tests undertaken on clinical grounds will be collected.

STUDY FLOW CHART 1A- Interim Extension

Screening
On or after Visit 7 / Treatment
Visit 8
(Baseline) / Visit 9
36 months / 42 months / 54 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medications review / X / X
Blood sample for serum / X
QOL questionnaires / X
Depression questionnaire / X
Parkinson’s Rating Score / X
Non-motor symptom score / X
PD grading / X
Parkinson’s sleep scale / X
Epworth sleep score / X
REM sleep disturbance / X
Impulsive questionnaire / X
Clinical and Global impression / X
Constipation questionnaire / X
Cognitive testing / X
Autonomic features / X
Wearing off questionnaire / X

STUDY FLOW CHART 1B – Years 6-9 Extension (Patients with Parkinson’s)

Visit 8 / Visit
9 / Visit
10 / Visit
11
42-48 months / 54 months / 72 months / 90 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medical/Disease history / X
Medications review / X / X / X / X
Vital signs (blood pressure, weight) / X / X / X
Blood sample for serum / X / X / X
QOL questionnaires / X / X / X
Depression questionnaire / X / X / X
Parkinson’s Rating Score / X / X / X
Non-motor symptom score / X / X / X
PD grading / X / X / X
Diagnostic features / X / X / X
Sleep questionnaires (Parkinson’s, Epworth) / X / X / X
Impulsivity questionnaire / X / X / X
Clinical Global impression / X / X
Cognitive testing / X / X / X
Autonomic score / X / X / X
Motor fluctuation questionnaire / X / X / X
Scans* / X / X
Communicate research blood test result / Done at next visit (V8, V9 or V10)
L-dopa test dose if not already done / X

* Structural and functional brain imaging. Results of tests undertaken on clinical grounds will be collected.

STUDY FLOW CHART 2- Patients with PD onset at less than age 50 years

Screening Visit 0 / (Baseline)Visit 1
0 months / Visit 2
6 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medical/Disease history / X
Medications review / X
Vital signs (blood pressure, weight, height / X
Family history / X
Demographics / X
Blood sample for DNA / X
Blood sample for serum / X
QOL questionnaires / X
Depression questionnaire / X
Parkinson’s Rating Score / X
Patient items – social history, non-motor symptoms / X
Parkinson’s medical items / X
PD grading / X
Parkinson’s sleep scale / X
Epworth sleep score / X
REM sleep disturbance / X
Impulsive questionnaire / X
Constipation questionnaire / X
Cognitive testing / X
Smell testing / X
Autonomic features / X
Environmental exposure questionnaire / X
Diagnostic factors / X
Scans* / X
Tissue Bank / X / X
Personality Questionnaire / X
Wearing off Questionnaire / X

* Structural brain imaging and functional brain imaging. Results of tests undertaken on clinical grounds will be collected.

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STUDY FLOW CHART 3- Relatives of PD patients

(Baseline) Visit 1 / Visit 2
0 months / 36 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medical history / X
Medications review / X / X
Vital signs (blood pressure, weight) / X / X
Height / X
Family history / X
Demographics / X
Blood sample for DNA / X
Blood sample for serum / X / X
Depression questionnaire / X / X
Parkinson’s Rating Score / X / X
Non-motor symptoms / X / X
Parkinson’s medical items / X / X
Parkinson’s sleep scale / X / X
Epworth sleep score / X / X
REM sleep disturbance / X / X
Impulsive questionnaire / X / X
Constipation questionnaire / X / X
Cognitive testing / X / X
Smell testing / X / X
Autonomic features / X / X
Global quality of life / X / X
Personality questionnaire / X
Environmental exposure questionnaire / X
Scans* / X / X
Tissue bank / X

*Structural brain imaging and functional brain imaging. Results of tests undertaken on clinical grounds will be collected.

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STUDY FLOW CHART 3A – Years 6-9 Extension (Siblings of PD Patients)

Visit 2 / Visit 3
36 months / 72 months
Obtain informed consent / X
Review Inclusion/Exclusion Criteria / X
Medical history / X
Medications review / X
Vital signs (blood pressure, weight) / X
Blood sample for serum / X
Depression questionnaire / X
Motor Rating Score / X
Non-motor symptoms questionnaire / X
Sleep questionnaires (Parkinson’s, Epworth) / X
Impulsivity questionnaire / X
Cognitive testing / X
Autonomic score / X
Global quality of life / X
Scans* / X
Communicate research blood test result / Done at next visit, V2 or V3

*Structural and functional brain imaging. Results of tests undertaken on clinical grounds will be collected.

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1.0INTRODUCTION

Parkinson’s disease epidemiology

Parkinson’s disease (PD) is a neurodegenerative disorder of increasing incidence and prevalence with advancing age. Between 4 and 20 new cases per 100,000 population are diagnosed each year. Prevalence is approximately 160 per 100,000 in the UK. Around 2% of people over 65 years have Parkinson’s disease. The cause of Parkinson’s disease is unknown but genetic and environmental causes have both been studied in some detail. The majority of Parkinson’s disease cases are sporadic, but a few are inherited. An individual with family history of Parkinson’s disease has an approximately doubling of the risk of Parkinson’s compared to the rate in the background population. Around 15% of patients have a positive family history of Parkinson’s disease. Gene mutations implicated in the development of Parkinson’s disease consist of autosomal dominant forms including PARK1 which codes for alpha-synuclein and autosomal recessive forms including PARK6 which codes for the PINK1 protein, and leucine-rich repeat kinase 2 (LRRK2). Some of the cases with gene mutations have variations in age of onset (earlier for PARK6 and PARK7, for example), while some have more problems of motor complication, for example there is more dystonia and more dyskinesia with PARK2. Some gene mutations are associated with a presentation very similar to what is considered to be classic idiopathic Parkinson’s disease, and this is the largely the case for age of onset for LRRK2 and clinical appearance, although even here there are some components showing variation, as detailed below.

Parkinson’s disease genetics

The gene discoveries in Parkinson’s disease have emerged from the study of Mendelian families, which carry rare highly penetrant genetic mutations. More recently genome wide association studies have identified common genetic variation, which increases the risk of developing PD. However, it is considered likely that there are genetic influences on the expression of components of the disease, such as the development and severity of dyskinesia, and the development of cognitive impairment and dementia. Accordingly it is thought valuable to characterize patients in detail from a clinical perspective, and to study groups of patients with variations in expression of their disease, alongside further genetic testing. Technical advances in gene tests allow enhancements in the process of gene discovery in relation to these sub-categories of Parkinson’s expression and severity. It is therefore the primary hypothesis of the present study that detailed profiling of patients with Parkinson’s disease will distinguish sub-types of clinical presentation relating to variations in motor, cognitive, therapy response, and non-motor features. It is considered likely that these features will have genetic influences which will be the focus of the present study.

Parkinson’s disease phenomenology

The PRoBaND study will therefore evaluate further around issues which have already shown some linkage to genetic test results, as follows:

Motor. PD can be broadly divided into tremor-dominant and postural instability gait disorder types (Jankovic et al 1990). A proportion of patients who are tremor-dominant have a more benign course (“benign tremulous PD”).
Cognitive sub-types. Neuropsychological tests show that early mild cognitive impairment gives an 88 times greater risk of dementia at 5 years compared to patients with normal baseline cognition (Williams-Gray et al 2009). Baseline results correlate with genetic variations in microtubule-associated protein tau (MAPT). There is partial correlation with genetic variability in the Valine/Methionine component of catecholOmethyltransferase (COMT) (Williams-Gray et al 2009).
Therapy response. The response to antiparkinson therapy varies from excellent to poor, partly due to coexisting disorders (e.g. cerebrovascular disease, Zijlmans et al 2004). Some patients develop early motor complications, while others are less fluctuant. There is surprisingly limited data about this variation. Biochemical and genetic mechanisms which are likely to underlie this variability require exploration, to find new (probably non-dopaminergic) drug mechanisms.
Non-motor features. These often predate motor features and may be important for example in first degree relatives. Non-motor severity is similar for young and older onset PD when gene test negative, with a range of severity (Chaudhuri and Schapira 2009). Non-motor involvement varies according to genetic sub-type, being significantly less in Parkin positive PD (Kagi et al, 2010). A lower prevalence of sleep disturbance was found in familial versus sporadic PD (Vibha et al 2010).

Genetic sub-types of PD

A proportion of PD patients tested carry highly penetrant pathogenic genetic variance. Some differences have been described in patients carrying specific mutations, although to date this has largely been based on retrospective case note review:

a)Patients positive for Leucine-rich repeat kinase 2 (LRRK2) have a similar onset age, but are more likely to develop dystonia after antiparkinson treatment is introduced, to have leg tremor, and progress more slowly (Healy et al, 2008).

b)Patients positive for Parkin have an earlier onset, and more dystonia (predating antiparkinson therapy). Greater baseline abnormalities are seen on nigrostriatal presynaptic dopamine brain scans, but the rate of progression (clinically and on imaging) is at least 5 times slower than that of idiopathic PD (Pavese et al, 2009). It is likely that genetic factors contribute in a far greater sense than currently understood, to PD expression across the above 4 domains. Understanding the links between gene defects and clinical expression is crucial in exploring the causes, and thereby finding new treatments, for PD.

Recording and scoring key PD features in the PRoBaND study

Multiple elements of varied clinical expression in PD and rates of change over time will be recorded using validated tools. PD gene tests will be run, for patients and first-degree relatives.